Different chronic cocaine administration protocols induce changes on dentate gyrus plasticity and hippocampal dependent behavior

Hippocampus is a limbic structure that participates in learning and memory formation. Specifically the dentate gyrus has been described as a hippocampal subregion with high rates of plasticity and it is targeted by different psychoactive drugs modulating synaptic plasticity. Repeated cocaine administration induces sensitization to the locomotor effects and it is believed that sensitization involves the same mechanisms of drug seeking and relapse. Although, the mechanisms underlying sensitization is not fully understood. In this work we investigated the impact of repeated intraperitoneal administration of cocaine (15 or 20 mg/kg/day along 5 or 15 days respectively; and 15 mg/kg/day along 5 day followed by a challenge dose after three days of withdrawal) on the dentate gyrus synaptic plasticity, differentiating between sensitized and nonsensitized rats. Furthermore, we correlated changes on the hippocampal synaptic plasticity to memory retention. Our results revealed that the prevalence of cocaine sensitization (around 50%) was identical in all protocols used. The results found in the threshold to generate LTP were similar for all protocols used, being the threshold values cocaine‐treated groups (sensitized and nonsensitized) significantly reduced compared to controls, observing the highest reduction in the sensitized group. Moreover, we observed a facilitated retention of recent memory formation only in sensitized animals the nonsensitized subjects remained at the control levels. In conclusion, sensitization to cocaine generates a high efficiency of hippocampal synaptic plasticity that may underlie the aberrant engagement of learning processes occurred during drug addiction. Synapse 64:742–753, 2010. © 2010 Wiley‐Liss, Inc.     

Enriched environment exposure regulates excitability, synaptic transmission, and LTP in the dentate gyrus of freely moving rats

Performance in hippocampus-dependent and other tasks can be improved by exposure to an enriched environment (EE), but the physiological changes in neural function that may mediate these effects are poorly understood. To date, there have been conflicting reports regarding potential mechanisms, such as an increase in basal synaptic transmission, an increase in cell excitability, or altered synaptic plasticity. Here, we reexamined in freely moving animals the conditions under which varying degrees of EE exposure might lead to increases in synaptic or neural function in the dentate gyrus of the hippocampus. Adult male Sprague-Dawley rats were chronically implanted with stimulating and recording electrodes in the perforant path and dentate gyrus, respectively, and housed singly in standard cages. After stable recordings were established for field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs), the effects of various degrees of periodic novel environment exposure for 19 days were assessed. Exposure to an EE increased fEPSPs, but only when animals were kept in nominally low-stress housing conditions. An increase in granule-cell excitability, as evidenced by PS increases, was induced by all environmental treatments with the greatest effect being induced by overnight EE exposure. EE exposure did not change the level of long-term potentiation (LTP) induced by a moderate high-frequency tetanus, but continued EE exposure post-tetanus produced a significantly faster decay of LTP relative to control animals. These results suggest that, in adult animals, EE exposure may augment hippocampal information processing, but may also speed turnover of information in the hippocampus during the maintenance period.     

Local infusion of ghrelin enhanced hippocampal synaptic plasticity and spatial memory through activation of phosphoinositide 3-kinase in the dentate gyrus of adult rats

Ghrelin, an orexigenic hormone, is mainly produced by the stomach and released into the circulation. Ghrelin receptors (growth hormone secretagogue receptors) are expressed throughout the brain, including the hippocampus. The activation of ghrelin receptors facilitates high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in vitro, and also improves learning and memory. Herein, we report that a single infusion of ghrelin into the hippocampus led to long-lasting potentiation of excitatory postsynaptic potentials (EPSPs) and population spikes (PSs) in the dentate gyrus of anesthetized rats. This potentiation was accompanied by a reduction in paired-pulse depression of the EPSP slope, an increase in paired-pulse facilitation of the PS amplitude, and an enhancement of EPSP-spike coupling, suggesting the involvement of both presynaptic and postsynaptic mechanisms. Meanwhile, ghrelin infusion time-dependently increased the phosphorylation of Akt-Ser473, a downstream molecule of phosphoinositide 3-kinase (PI3K). Interestingly, PI3K inhibitors, but not NMDA receptor antagonist, inhibited ghrelin-induced potentiation. Although ghrelin had no effect on the induction of HFS-induced LTP, it prolonged the expression of HFS-induced LTP through extracellular signal-regulated kinase (ERK)1/2. The Morris water maze test showed that ghrelin enhanced spatial memory, and that this was prevented by pretreatment with PI3K inhibitor. Taken together, the findings show that: (i) a single infusion of ghrelin induced a new form of synaptic plasticity by activating the PI3K signaling pathway, without HFS and NMDA receptor activation; (ii) a single infusion of ghrelin also enhanced the maintenance of HFS-induced LTP through ERK activation; and (iii) repetitive infusion of ghrelin enhanced spatial memory by activating the PI3K signaling pathway. Thus, we propose that the ghrelin signaling pathway could have therapeutic value in cognitive deficits.     

Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement

Thyroid hormone activates extracellular signal-regulated kinases (ERK1 and ERK2), which are important in late long-term potentiation (L-LTP). The aim of this study was to determine the possible mechanism underlying the impairment of L-LTP as a result of hypothyroidism. We investigated the effect of hypothyroidism on L-LTP of the two associative pathways in the hippocampus: the Schaffer collateral synapses and the perforant path synapses. We also examined the effect of hypothyroidism on ERK1 and ERK2 levels in both the CA1 and dentate gyrus (DG) regions of the hippocampus. Electrophysiological recordings from hippocampi of anesthetized rats show that hypothyroidism impairs L-LTP in CA1 region, but not in the DG. Western blot analysis of the CA1 region shows that hypothyroidism decreases phosphorylated ERK1 and ERK2 levels without affecting their total levels. In the DG of the hypothyroid rat, however, there was no significant change in the levels of phosphorylated or total ERKs. The correlation between the effect of hypothyroidism on L-LTP and enzyme levels suggests that hypothyroidism-induced impairment of L-LTP in CA1 may be due to decreased levels of phosphorylated ERK1 and ERK2.     

Mouse models of impaired fear memory exhibit deficits in amygdalar LTP

Inbred mouse strains have different genetic backgrounds that can result in impairments of synaptic plasticity and memory. They are valuable models for probing the mechanisms of memory impairments. We examined fear memory in several inbred strains, along with synaptic plasticity that may underlie fear memory. Long-term potentiation (LTP) is a form of activity-dependent synaptic plasticity that is a candidate cellular mechanism for some forms of learning and memory. Strains with impaired contextual or cued fear memory may have selective LTP deficits in different hippocampal subregions, or in the amygdala. We measured fear memory and its extinction in five inbred strains: C57BL/6NCrlBR (B6), A/J, BALB/cByJ (BALB), C57BL/10J (B10), and SM/J (SM). We also measured LTP in the basolateral amygdala and in the hippocampal Schaeffer collateral-commissural (SC) and medial perforant pathways (MPP). All strains exhibited intact contextual fear memory 24 h post-training, but cued fear memory was impaired in strains A/J, BALB, and SM. At 1 h post-training, both contextual and cued fear memory deficits were more widespread: all strains except for B6 and B10 showed impairments of both types of memory. Contextual fear extinction was impaired in BALB and SM. We found that amygdalar LTP was reduced in strains A/J and BALB, but SC LTP was intact in all strains (except for a selective multi-train LTP impairment in BALB). MPPLTP was similar in all five strains. Thus, reduced amygdalar LTP is correlated with impaired cued fear memory in strains A/J and BALB. Also, hippocampal SC LTP is more strongly correlated with 24-h (long-term) than with 1-h (short-term) contextual fear memory. In this first conjoint study of amygdala-dependent memory and amygdalar LTP in inbred mice, we identified specific hippocampal and amygdalar LTP deficits that correlate with fear memory impairments. These deficits should be considered when selecting inbred strains for genetic modification.     

Synaptic loss and retention of different classic cadherins with LTP‐associated synaptic structural remodeling in vivo

Cadherins are synaptic cell adhesion molecules that contribute to persistently enhanced synaptic strength characteristic of long‐term potentiation (LTP). What is relatively unexplored is how synaptic activity of the kind that induces LTP‐associated remodeling of synapse structure affects localization of cadherins, particularly in mature animals in vivo, details which could offer insight into how different cadherins contribute to synaptic plasticity. Here, we use a well‐described in vivo LTP induction protocol that produces robust synaptic morphological remodeling in dentate gyrus of adult rats in combination with confocal and immunogold electron microscopy to localize cadherin‐8 and N‐cadherin at remodeled synapses. We find that the density and size of cadherin‐8 puncta are significantly diminished in the potentiated middle molecular layer (MML) while concurrently, N‐cadherin remains tightly clustered at remodeled synapses. These changes are specific to the potentiated MML, and occur without any change in density or size of synaptophysin puncta. Thus, the loss of cadherin‐8 probably represents selective removal from synapses rather than overall loss of synaptic junctions. Together, these findings suggest that activity‐regulated loss and retention of different synaptic cadherins could contribute to dual demands of both flexibility and stability in synapse structure that may be important for synaptic morphological remodeling that accompanies long‐lasting plasticity. © 2010 Wiley Periodicals, Inc., Inc.     

Long- and short-term plasticity at mossy fiber synapses on mossy cells in the rat dentate gyrus

Mossy cells give rise to the commissural and associational pathway of the dentate gyrus, and receive their major excitatory inputs from the mossy fibers of granule cells. Through these feed-back excitatory connections, mossy cells have been suggested to play important roles in both normal signal processing in learning and memory, as well as in seizure propagation. However, the nature of the activity-dependent modifications of the mossy fiber inputs to mossy hilar cells is not well understood. We studied the long- and short-term plasticity properties of the mossy fiber-mossy cell synapse, using the minimal stimulation technique in slices in whole cell recorded mossy cells retrogradely prelabeled with the fluorescent dye DiO from the contralateral dentate gyrus. Following tetanic stimulation, mossy fiber synapses showed significant NMDA receptor-independent long-term potentiation (LTP), associated with increased excitatory postsynaptic currents (EPSC) amplitude and decreased failure rates. Coefficient of variance and failure rate analyses suggested a presynaptic locus of LTP induction. Mossy fiber synapses on mossy cells also showed activity-dependent short-term modification properties, including both frequency-dependent facilitation (stimuli at higher frequencies evoked larger EPSCs with lower failure rates) and burst facilitation (each EPSC in a burst had a larger amplitude and higher probability of occurrence than the preceding EPSCs within the burst). The data show that mossy fiber-mossy cell synapses exhibit both long- and short-term plasticity phenomena that are generally similar to the mossy fiber synapses on CA3 pyramidal cells.     

Large-scale study of phosphoproteins involved in long-term potentiation in the rat dentate gyrus in vivo

The mechanisms underlying the induction of synaptic plasticity and the formation of long-term memory involve activation of cell-signalling cascades and protein modifications such as phosphorylation and dephosphorylation. Based on a protein candidate strategy, studies have identified several protein kinases and their substrates, which show an altered phosphorylation state during the early phases of long-term potentiation (LTP), yet only a limited number of synaptic phosphoproteins are known to be implicated in LTP. To identify new phosphoproteins associated with LTP, we have undertaken a proteomic study of phosphoproteins at different time points following the induction of LTP in the dentate gyrus in vivo (0, 15 and 90 min). For each time point, proteins from the dentate gyrus were separated by two-dimensional gel electrophoresis and stained with Pro−Q^® Diamond, a fluorescent stain specific for phosphoproteins. Fourteen proteins whose phosphorylation state varied significantly following LTP were identified using matrix-assisted laser desorption ionization/time of flight mass spectrometry and electrospray ionization-Orbitrap tandem mass spectrometry (MS/MS). They are involved in various cellular functions implicated in synaptic plasticity, such as intracellular signalling, axonal growth, exocytosis, protein synthesis and metabolism. Our results highlight new proteins whose phosphorylation or dephosphorylation is associated with LTP induction or maintenance. Further studies focusing on the regulation of specific phosphorylation sites will lead to greater understanding of the individual implications of these proteins in LTP as well as of their molecular interactions.     

Brief novelty exposure facilitates dentate gyrus LTP in aged rats

Aging is associated with a decreased capacity for dentate gyrus (DG) granule cell depolarization as well as reduced perforant path activation. Although it is well established that the maintenance of DG long-term potentiation (LTP) over days is impaired in aged, as compared to young animals, the threshold for inducing this LTP has never been investigated in aged, awake animals. In addition, although exposure to novelty prior to theta-burst stimulation (TBS) increases both the induction and longevity of DG LTP in adult rats, the effects of exposure to novelty on LTP in aged rats have never been investigated. Here, we report that although TBS delivered in the home cage induces robust and long-lasting DG LTP in young rats, TBS fails to induce DG LTP in aged rats. Interestingly, delivery of TBS to aged rats exploring novel environments induces robust and long-lasting LTP, with the induction, but not the longevity, of this LTP being similar in magnitude to that observed in young rats delivered TBS in the home cage. These results indicate that although TBS-induced DG LTP is impaired in aged, as compared to young rats, TBS during exploration of novel environments is sufficient to rescue age-related deficits in DG LTP. We discuss these observations in the context of previous findings suggesting that the facilitation of LTP by exposure to novel environments results as a consequence of reduced network inhibition in the DG and we suggest that, in spite of age-related changes in the DG, this capacity persists in aged rats and represents a nondietary and nonpharmacological way to facilitate DG LTP during aging.     

Differential long-term depression in CA3 but not in dentate gyrus following low-frequency stimulation of the medial perforant path

Synaptic plasticity may depend not only on the afferent fibers but also on the recipient structure. The medial perforant path (MPP) from the entorhinalcortex projects to both the dentate gyrus (DG) and CA3, resulting in excitatory postsynaptic potentials (EPSPs) in both areas. In this study, we showed that long-term depression (LTD) following low-frequency stimulation of MPP was found only in CA3a, a CA3 subfield, but not in DG. Field potentials were recorded and current source density (CSD) analyzed in CA3a and DG following stimulation of MPP in urethane-anesthetized rats. MPP evoked a short-latency population spike (PS) and EPSP in CA3a, <2.5 ms delayed from the respective events in DG. A small electrolytic lesion of CA3a abolished the locally recorded PS in CA3a but did not affect the responses in the DG. Low-frequency stimulation of the MPP for 600 pulses at 5 Hz, but not at 1 Hz, resulted in LTD of up to 2 h in CA3a but not in DG. High-frequency stimulation (400 Hz bursts) of the MPP resulted in long-term potentiation (LTP) in both CA3a and DG. LTD at CA3a was blocked by a prior intracerebroventricular administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist DL-2-amino-5-phosphonovaleric acid or a nonselective group I/II metabotropic glutamate receptor (mGluR) antagonist (RS)-α-methyl-4-carboxyphenylglycine. We conclude that an NMDAR and mGluR sensitive LTD is induced in CA3 but not in the DG following low-frequency MPP stimulation in vivo, and the bi-directional synaptic plasticity in CA3 may be responsible for its behavioral functions.     

Chronic in vivo optogenetic stimulation modulates neuronal excitability,spine morphology,and Hebbian plasticity in the mouse hippocampus

Prolonged increases in excitation can trigger cell‐wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes, and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 hr of stimulation with 15‐ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin‐2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2‐expressing mice immediately after the end of stimulation. Finally, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.     

Dissociation between apoptosis, neurogenesis, and synaptic potentiation in the dentate gyrus of adrenalectomized rats

Removal of adrenal hormone corticosterone in rats aged 3-4 months results within 3 days in acceleration of apoptosis and proliferation of newborn cells in the dentate gyrus (DG). A critical question is whether such a shift in the maturity of dentate cells after adrenalectomy (ADX) affects synaptic plasticity. To address this question, male rats were adrenalectomized and synaptic potentiation was recorded in vitro in hippocampal slices, as well as in vivo, in response to high frequency stimulation of the perforant path, 3 days after ADX. At this time-point, cell loss was assessed and proliferation was examined. Based on two independent parameters, bromodeoxyuridine and Ki-67, we found that removal of the adrenal glands increases proliferation rate. This increase in proliferation was, in particular, evident in those animals that displayed substantial cell loss. The accelerated cell-turnover after ADX was accompanied by reduced synaptic potentiation, both when recorded in vitro and in vivo. Corticosterone replacement in vivo (in adrenalectomized animals), at levels that activate the mineralocorticoid receptor, prevented ADX-induced proliferation, apoptosis, and restored synaptic potentiation to control levels. Importantly, corticosterone applied to slices from adrenalectomized rats also normalized synaptic potentiation, despite increased proliferation. This suggests that changes in cell proliferation and apoptotic cell death in the DG are not necessarily key factors determining the efficacy of synaptic potentiation.     

Cocaine decreases the expression of PSA-NCAM protein and attenuates long-term potentiation via glucocorticoid receptors in the rat dentate gyrus

The present study investigated a potential role for glucocorticoid (GR) and mineralocorticoid (MR) receptors in the detrimental effects of single cocaine (COC) administration on both the number of polysialylated neural cell adhesion molecule (PSA-NCAM)-positive neurons and the induction of long-term potentiation (LTP) in the rat dentate gyrus (DG). The effects of COC (15 mg/kg i.p.) on the number of PSA-NCAM-positive neurons and the induction of LTP observed 2 days after COC administration were abolished either by depleting circulating corticosterone after administration of metyrapone (100 mg/kg s.c. given 3 h before COC) or by pharmacologically blocking GRs using mifepristone (RU 38486, 10 mg/kg s.c. given 1 h before COC). Administration of the MR blocker spironolactone (50 mg/kg s.c. given 1 h before COC) did not alter the effects of COC on the number of PSA-NCAM-positive neurons or LTP induction. Results have also shown that COC does not change the rate of cell proliferation, as measured by the presence of Ki-67 and the incorporation of bromodeoxyuridine (100 mg/kg i.p. given 2 h after COC) into the newly born cells in the DG 2 days after COC administration. Finally, we observed that GRs colocalized with some, but not all, PSA-NCAM-positive neurons, whereas MRs showed no colocalization with neurons positive for PSA-NCAM in the DG. These data indicate that a single dose of COC may arrest hippocampal susceptibility to plastic changes and lead to functional impairments through the alteration of hippocampal structure and the formation of memory traces.     

PSA-NCAM immunocytochemistry in the cerebral cortex and other telencephalic areas of the lizard Podarcis hispanica: differential expression during medial cortex neuronal regeneration

The lizard medial cortex, a region homologous to the mammalian dentate gyrus, shows postnatal neurogenesis and the surprising ability to replace its neurons after being lesioned specifically with the neurotoxin 3-acetylpyridine. As the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is expressed during neuronal migration and differentiation, we have studied its distribution in adult lizards and also during the lesion-regeneration process. In the medial cortex of control animals, many labeled fusiform somata, presumably corresponding to migratory neuroblasts, appeared in the inner plexiform layer. There were also scattered immunoreactive granule neurons in the cell layer. Double immunocytochemistry with 5'-bromodeoxyuridine revealed that some of the PSA-NCAM-expressing cells in the inner plexiform and cell layers were generated recently. PSA-NCAM immunoreactivity was also present in the dorsomedial, dorsal, and lateral cortices, as well as in the dorsal ventricular ridge, the nucleus accumbens, and the nucleus sphericus. Twelve hours after the injection of 3-acetylpyridine, some medial cortex granule neurons appeared degenerated, although some of them still expressed PSA-NCAM. One to 2 days after the injection, most granule neurons appeared degenerated and no PSA-NCAM immunoreactivity was detected in the medial cortex cell layer. Four to 7 days after treatment, abundant labeled fusiform cells populated the inner plexiform layer and some immunoreactive somata were seen in the cell layer. Fifteen to 30 days after the neurotoxin injection, the number of PSA-NCAM expressing granule neurons augmented considerably and the level was still above control levels in lizards that survived 42 days. Our results show for the first time the expression of PSA-NCAM in a reptile brain, where it appears to participate in the migration and differentiation of granule neurons during adult neurogenesis and regeneration.     

Polysialylated neural cell adhesion molecule expression by neurons and astrolial molecule in the rat dentate gyrus declines dramatically with increasing age

The expression of polysialylated neurons in the dentate gyrus of the hippocampal formation of young (postnatal day 40), mature (postnatal day 80) and aged (postnatal day 540) male Wistar rats has been investigated by immunohistochemical techniques employing a monoclonal antibody specific for neural cell adhesion molecule-linked α2,8 polysialic acid. A strong immunoreactivity was found on the cell bodies, dendrites and axons of granule-like neuronal cells at the border between the hilar region and the granule cell layer of the young rat. In the mature animal the number of immunoreactive neurons declined dramatically and were virtually absent in the aged group. Using an alternative fixation procedure, glial fibrillary acidic protein-positive and polysialylated astroglia processes were found in close proximity to the dendrites of the polysialylated granule-like cells. The number of astroglial processes traversing the granule cell layer showed a similar age-dependent decline to that observed with the polysialylated neurons. Glial fibrillary acidic protein-positive and polysialylated stellate astroglia were present throughout the hippocampal formation, but did not show the marked age-dependent decline observed with the astroglial processes in the granule cell layer.The neuronal dendrites and astroglial processes exhibited a strict numerical ratio in the young and mature animal and, in double immunofluorescence studies with anti-polysialic acid and anti-glial fibrillary acidic protein, the astroglial processes exhibited apparent points of cell and/or dendritic contact. These findings suggest that loss of polysialylated astroglial processes precedes the decline in polysialylated dentate neurons.     

Experimental hypothyroidism delays field excitatory post-synaptic potentials and disrupts hippocampal long-term potentiation in the dentate gyrus of hippocampal formation and Y-maze performance in adult rats

Manipulations of thyroid hormones have been shown to influence learning and memory. Although a large body of literature is available on the effect of thyroid hormone deficiency on learning and memory functions during the developmental stage, electrophysiological and behavioural findings, particularly on propylthiouracil administration to adult normothyroid animals, are not satisfactory. The experiments in the present study were carried out on 12 adult male Wistar rats aged 6-7 months. Hypothyroidism was induced by administering 6-n-propyl-2-thiouracil in their drinking water for 21 days at a concentration of 0.05%. The spatial learning performance of hypothyroid and control rats was studied on a Y-maze. The rats were then placed in a stereotaxic frame under urethane anaesthesia. A bipolar tungsten electrode was used to stimulate the medial perforant path. A glass micropipette was inserted into the granule cell layer of the ipsilateral dentate gyrus to record field excitatory post-synaptic potentials. After a 15-min baseline recording of field potentials, long-term potentiation was induced by four sets of tetanic trains. The propylthiouracil-treated rats showed a significantly attenuated input-output (I/O) relationship when population spike (PS) amplitudes and field excitatory post-synaptic potentials (fEPSP) were compared. fEPSP and PS latencies were found to be longer in the hypothyroid group than in the control group. The PS amplitude and fEPSP slope potentiations in the hypothyroid rats were not statistically different from those in the control rats, except for the field EPSP slope measured in the post-tetanic and maintenance phases. The hypothyroid rats also showed lower thyroxine levels and poor performance in the spatial memory task. The present study provides in vivo evidence for the action of propylthiouracil leading to impaired synaptic plasticity, which might explain deficit in spatial memory tasks in adult hypothyroid rats.     

Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation

Aging is associated with an impaired ability to maintain long-term potentiation (LTP), but the underlying cause of the impairment remains unclear. To gain a better understanding of the cellular and molecular mechanisms responsible for this impairment, the synaptic transmission and plasticity were studied in the CA1 region of hippocampal slices from adult (6-8 months) and poor-memory (PM)-aged (23-24 months) rats. The one-way inhibitory avoidance learning task was used as the behavioral paradigm to screen PM-aged rats. With intracellular recordings, CA1 neurons of PM-aged rats exhibited a more hyperpolarized resting membrane potential, reduced input resistance, and increased amplitude of afterhyperpolarization and spike threshold, compared with those in adult rats. Although a reduction in the size of excitatory synaptic response was observed in PM-aged rats, no obvious differences were found between adult and PM-aged rats in the pharmacological properties of excitatory synaptic response, paired-pulse facilitation, or frequency-dependent facilitation, which was tested with trains of 10 pulses at 1, 5, and 10 Hz. Slices from the PM-aged rats displayed significantly reduced early-phase long-term potentiation (E-LTP) and late-phase LTP (L-LTP), and the entire frequency-response curve of LTP and LTD is modified to favor LTD induction. The susceptibility of time-dependent reversal of LTP by low-frequency afferent stimulation was also facilitated in PM-aged rats. Bath application of the protein phosphatase inhibitor, calyculin A, enhanced synaptic response in slices from PM-aged, but not adult, rats. In contrast, application of the cAMP-dependent protein kinase inhibitors, Rp-8-CPT-cAMPS and KT5720, induced a decrease in synaptic transmission only in slices from the adult rats. Furthermore, the selective beta-adrenergic receptor agonist, isoproterenol, and pertussis toxin-sensitive G-protein inhibitor, N-ethylmaleimide, effectively restored the deficit in E-LTP and L-LTP of PM-aged rats. These results demonstrate that age-related impairments of synaptic transmission and LTP may result from alterations in the balance of protein kinase/phosphatase activities.